The mitochondrial electron transport (or respiratory) chain is a series of enzyme complexes in the mitochondrial membrane that is responsible for the transport of electrons from NADH to oxygen and the coupling of this oxidation to the synthesis of ATP (oxidative phosphorylation). ATP then provides the primary source of energy for driving a cell's many energy-requiring reactions.
ATP synthase (F.sub.0 F.sub.1 ATPase) is the enzyme complex at the terminus of this chain and serves as a reversible coupling device that interconverts the energies of an electrochemical proton gradient across the mitochondrial membrane into either the synthesis or hydrolysis of ATP. This gradient is produced by other enzymes of the respiratory chain in the course of electron transport from NADH to oxygen. When the cell's energy demands are high, electron transport from NADH to oxygen generates an electrochemical gradient across the mitochondrial membrane. Proton translocation from the outer to the inner side of the membrane drives the synthesis of ATP. Under conditions of low energy requirements and when there is an excess of ATP present, this electrochemical gradient is reversed and ATP synthase hydrolyzes ATP. The energy of hydrolysis is used to pump protons out of the mitochondrial matrix.
ATP synthase is, therefore, a dual complex, the V portion of which is a transmembrane proton carrier or pump, and the F.sub.1 portion of which is catalytic and synthesizes or hydrolyzes ATP. The mammalian ATP synthase complex from bovine heart mitochondria consists of sixteen different polypeptides (Walker, J. E. and Collinson, T. R. (1994) FEBS Lett.346: 39-43). Six of these polypeptides (subunits .alpha., .beta., .gamma., .delta., .epsilon., and an ATPase inhibitor protein, IF.sub.1) comprise the globular catalytic F.sub.1 ATPase portion of the complex, which lies outside of the mitochondrial membrane. The remaining ten polypeptides (subunits a, b, c, d, e, f, g, F6, OSCP, and A6L) comprise the proton-translocating, membrane spanning F.sub.0 portion of the complex. Most of the subunits of bovine ATP synthase are related to subunits of the bacterial and chloroplast complexes, and presumably have functions similar to these homologs. However subunits F6, A6L, d, and e have no such obvious counterparts (Walker, J. E. et al. (1991) Biochemistry 30:5369-78). F6 is essential for binding F1 to the membrane sector of the complex and may have a regulatory function, but the functions of subunits A6L, d, and e are obscure. It is proposed that the d subunit is located in the stalk region of the ATP synthase complex between the F1 and F0 portions and may interact directly with ATP (Motojima, K. and Imanaka, T. (1992) Biochem. and Biophys. Res. Commun. 182(3):1130-38).
Like other members of the respiratory chain, all but two of the polypeptide subunits of ATP synthase are nuclear gene products that are imported into the mitochondria; subunits a and A6L are products of mitochondrial genes. Enzyme complexes similar to mammalian ATP synthase are found in all cell types and in chloroplast and bacterial membranes. This universality indicates the central importance of this enzyme to ATP metabolism.
Transcriptional regulation of these nuclear encoded genes appears to be the predominant means for controlling the biogenesis of ATP synthase. Defects and altered expression of ATP synthase and other enzymes in the respiratory chain are associated with a variety of disease conditions in man, including neurodegenerative diseases, myopathies, and cancer.
The discovery of polynucleotides encoding ATP synthase, and the molecules themselves provides a means to investigate the control of cellular respiration under normal and disease conditions. Such molecules related to ATP synthase satisfy a need in the art by providing new diagnostic or therapeutic compositions useful in cancer, neurodegenerative diseases, myopathies, and immunological disorders.